Cancer researchers are working toward a future in which each patient’s tumor will act like a crystal ball, revealing how oncologists should treat the cancer to obtain the best outcome.

Currently, physicians cannot predict which patients with prostate cancer should receive extra therapy after surgery - or whether some of these patients have an indolent disease that does not even require surgery. Most patients with colorectal cancer have surgery, but some, even at the earliest stages, could benefit from additional treatment - if physicians only knew who. Some of the genes and proteins specific to cancer cells can be used for prognostic purposes, as can the newest type of biomarker, mcro-RNAs, according to studies presented today at the 97th Annual Meeting of the American Association for Cancer Research.

Oncologists say it is very difficult to predict which patients with colorectal cancer will be cured by surgery alone - the single treatment most patients receive - and who might benefit from the addition of chemotherapy. Now, however, a Danish research team has found that just four protein biomarkers can predict death from colorectal cancer, independent of the stage or location of the cancer, or the age or gender of the patient.

In this study, blood taken from 654 colorectal cancer patients just before they had surgery was retrospectively analyzed for expression of the proteins. The test was not perfect, but it significantly identified the 308 patients who later died of the disease, some up to nine years later.

"The results show that the outcome of a significant number of patients was correctly identified, independent of stage and location," said the lead author, Hans J. Nielsen, M.D, DMSc., Professor of Surgical Oncology, at Hvidovre University Hospital.

When tumor stage and location were factored into the test, the concordance between predicted survival and actual survival was 79 percent, Nielsen said.

Such a test could offer prognostic value to clinicians who are unsure whether to treat their newly diagnosed patients with surgery alone, he said.

"This protein profile might be used to identify groups of patients who, independent of stage, should be offered adjuvant chemotherapy, and groups of patients who should not be offered chemotherapy," Nielsen said. "Such possible patient differentiation should, of course, be confirmed in prospective studies."

Such a study is currently underway in Denmark and other Scandinavian countries, he said. Up to 1,500 patients will be enrolled and blood samples will be collected periodically, such as before and after every treatment. The four protein markers will then be validated for disease stage, primary and secondary treatment, recurrence, and survival, and may prove to be predictive of response to individual therapies, as well as survival, Nielsen said.

The protein markers included in the test - TIMP-1, PAI-1, MASP-2, and CRP - are related to tissue remodeling, angiogenesis, and inflammation. The test uses antibodies that specifically bind to the proteins, and can analyze the actual concentration of these proteins.

Most researchers use gene or protein "chips" to define cancer processes, but researchers at Thomas Jefferson University in Philadelphia took a novel approach using a micro-RNA (miRNA) chip to help them understand how colon cancer develops. They found a distinct "signature" in the expression of miRNAs that predicts colon cancer.

Scientists have only recently discovered that miRNAs, which are tiny snippets of single-stranded RNA, can regulate the expression of genes, and thus regulate protein synthesis that affects cellular pathways. Because of this ability to regulate gene expression, miRNAs are believed to play an important role in cancer development, and could serve as targets for novel anti-cancer drugs.

To discover which miRNAs are expressed in colon cancer, compared to normal colon tissue, researchers at Thomas Jefferson University used a microarray chip containing probes for most of the known miRNAs in human and mouse. The investigative team, led by Bruce Boman, M.D., Ph.D., director of Genetic and Preventive Medicine at Jefferson, used the array to first characterize the miRNA expression pattern in intestinal epithelium purified from normal colon tissue.

This epithelial inner lining of the colon contains about 50 million test-tube shaped crypts that line the colon. Colon cancer arises in these crypts, and researchers believe that the cells of origin are the 10-20 immortal stem cells that reside at the bottom of each crypt. The job of these stem cells is to replenish the entire lining of the colon that turns over every five days. However, a mutation in these stem cells produces mutant daughter cells, disorganized tissue architecture, and increased proliferation of crypt cells, which leads to development of colon tumors, Boman said. Hence, they then analyzed malignant colon tissues and found that there are a number of miRNAs that were changed in expression in colon cancer.

Boman, who also directs the G.I. Cancer Program at Jefferson’s Kimmel Cancer Center, next purified and microdissected colonic crypts, and compared miRNA expression between the bottom tenth of the crypt, where the stem cells reside, and the upper 9/10s of the crypt. The difference in miRNA signatures between these two crypt regions, they reasoned, would distinguish stem cell from non-stem cell activity. They found a distinct signature of 16 miRNAs that characterizes the crypt bottom. Further analysis revealed that the expression pattern of these 16 miRNAs accurately predicted which colon tissues were normal and which cancerous. "Because this subset of miRNAs is differentially expressed at the crypt bottom, these miRNAs may be involved in regulating crypt stem cell population dynamics and contribute to the stem cell origin of colon cancer," Boman said.

"Our finding of a difference between miRNA expression in normal versus cancerous colon tissues should provide insight into mechanisms of colon cancer development and identify novel drugs to treat the disease" he said.

Researchers say that a chip that measures expression of 16 genes provides much needed prognostic information for prostate cancer patients who fall in the "gray zone" of traditional tests.

This experimental "universal bead array" test, which is designed to be low cost and easy to administer, appears to be a better predictor of relapse and disease-free survival than the Gleason Score, according to lead author Jessica Wang-Rodriguez, M.D., associate clinical professor of Pathology at the University of California, San Diego.

The 50 year-old Gleason Score, which assigns a progressive score of 1-10, based on how differentiated the cells look in a prostate cancer sample, works fairly well when the score is either very low or very high, but the prognosis for men who have scores in the mid-range is difficult to predict, Wang-Rodriguez said.

"It is very difficult to predict relapse and cancer recurrence in men who have a score of 6 or 7," she said. "Half of patients with these scores do well, and the other half don’t, but we cannot now predict who will fall into those groups."

Believing that a gene microarray test might provide additional information, a team of researchers led by Wang-Rodriguez picked 512 genes from the scientific literature that seemed to play a role in prostate cancer. They tested their expression on paraffin-embedded tumor samples taken from 71 patients, as well as on 41 control samples (non-cancerous prostate tissue taken from the same group of patients).

From this, they identified 16 candidate genes to further analyze. Ten of the genes were positively correlated to cancer progression, and six were negatively correlated, she said, and when tested, the combination generated a gene expression score that provided a better predictor of relapse than the Gleason score. "This gene expression score appears to give us additional prognostic information that current technology cannot provide, and that will help us treat patients accordingly," she said.

The assay they used was developed by Illumina Inc., of San Diego, which also funded this study. It uses fine optic beads and needs only tiny amount of DNA and RNA, Wang-Rodriguez said, and up to 96 different tests can be put on a single tray. "Having batches of samples together in a single assay that can then be read automatically makes it easy for routine clinical use," she said. "The test has a lot of potential, but needs to be further studied and validated."

Researchers have found that a test checking the methylation of a single gene can predict recurrence of prostate cancer in patients who have had their glands surgically removed.

In a clinical study of tumor tissue taken from 605 prostate cancer patients, those who had a positive PITX2 methylation test were three times more likely to experience cancer recurrence than those who tested negative, according to the study’s lead author, Susan Cottrell, Ph.D., senior scientist at Epigenomics, Inc., in Seattle. Furthermore, the test predicted recurrence in all patient subgroups, including patients with organ-confined and non-organ-confined disease.

Cancer recurrence was defined in this study as a rise in prostate specific antigen (PSA) levels after surgery, she said. Rising PSA after removal of the prostate indicates that the cancer is in the process of recurring.

"A methylation test like this could potentially help doctors decide which patients need additional treatment after surgery, and which probably don’t," said Cottrell. "The test is based on underlying molecular changes involved in cancer development, and this molecular information is complementary to the clinical and anatomical information currently used to predict recurrence, such as tumor stage and Gleason score."

According to Cottrell, the test will soon be validated in a multi-center trial for submission to the FDA. She also added that while this study analyzed prostatectomy samples, Epigenomics is expanding its research to see if the same results can be obtained from prostate biopsies. "If the test is a strong enough predictor of a good prognosis at the stage of biopsy, men with indolent cancer may not need surgery or radiation at all," she said.

"We know many men have a non-aggressive form of prostate cancer, but because we currently have no way to those patients, only very few are treated with a ’watchful waiting’ approach instead of surgery or radiation," she said.

The PITX2 gene is believed to play a role in regulation of hormones, and Epigenomics earlier found that it could also help predict recurrence in breast cancer patients.

In this study, the researchers tested a total of six genetic markers - PITX2 plus five other methylated genes that were identified in tumor tissue taken from patients who recurred shortly after surgery. Hypermethylation of all six markers correlated with poor survival, but using PITX2 alone, the researchers found they could develop a methylation score that defined a good prognosis (with 94 percent PSA-free survival 10 years after surgery) and a poor prognosis group (with 70 percent survival).

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